Phase 1-2 MAHCT w/ TCell Depleted Graft w/ Simultaneous Infusion Conventional and Regulatory T Cell

Phase 1

Completed

Conditions: Acute Leukemia
Myelodysplastic Syndromes (MDS)
Acute Myelogenous Leukemia
Myeloid Leukemia, Chronic
Acute Lymphoblastic Leukemia (ALL)
Acute Myeloid Leukemia
Chronic Myelogenous Leukemia
Lymphoma, Non-Hodgkin
Myeloproliferative Syndrome

Interventions: Biological: CD34+ Hematopoietic Progenitor Cells (HSPC)
Biological: Conventional T cells (Tcon) and Regulatory T cells (Treg)
Biological: Regulatory T-Cells (Treg)
Biological: Conventional T-Cells (Tcon)
Procedure: Myeloablative Conditioning Regimen

Registration Number: NCT01660607

Lead Sponsor: Stanford University

Brief Summary: This study looks at giving specific types of immune cells, called regulatory T cells and conventional T cells, to patients with blood cancers who are receiving a stem cell transplant. These cells are added back to help the immune system recover and reduce complications after the transplant.

Detailed Description: Primary Objectives:

* To determine the efficacy, safety and feasibility of administration of several dose combinations of conventional T cells (Tcon) and regulatory T cells (Treg) in patients undergoing allogeneic hematopoietic cell transplantation (HCT) with HLA matched donors (related or unrelated) using a T cell depleted graft \[CD34+ hematopoietic progenitor cells ("CD34+ HSPC")\], without immune suppression.

* To determine the maximum tolerated dose of infused regulatory and conventional T cells in the matched donor setting

* To determine 1 year event free survival (EFS) post HCT

Secondary Objectives:

* To determine the 1 year OS in patients undergoing allogeneic HCT with matched donors.

* To measure the incidence and severity of acute and chronic graft vs host disease (GvHD)

* To measure incidence of serious infections

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 68

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Phase 1: Low Dose Treg + Tcon	CD34+ Hematopoietic Progenitor Cells (HSPC)	Participants receive low-dose Treg (1e6 cells/kg) and Tcon (1e6 cells/kg) with CD34+ HSPC.
Phase 1: Low Dose Treg + Tcon	Regulatory T-Cells (Treg)	Participants receive low-dose Treg (1e6 cells/kg) and Tcon (1e6 cells/kg) with CD34+ HSPC.
Phase 1: Low Dose Treg + Tcon	Conventional T-Cells (Tcon)	Participants receive low-dose Treg (1e6 cells/kg) and Tcon (1e6 cells/kg) with CD34+ HSPC.
Phase 1: Low Dose Treg + Tcon	Myeloablative Conditioning Regimen	Participants receive low-dose Treg (1e6 cells/kg) and Tcon (1e6 cells/kg) with CD34+ HSPC.
Phase 1: Mid Dose Treg + Tcon	CD34+ Hematopoietic Progenitor Cells (HSPC)	Participants receive low-dose Treg (1e6 cells/kg), Tcon (1e6 cells/kg), and CD34+ HSPC following a conditioning regimen.
Phase 1: Mid Dose Treg + Tcon	Regulatory T-Cells (Treg)	Participants receive low-dose Treg (1e6 cells/kg), Tcon (1e6 cells/kg), and CD34+ HSPC following a conditioning regimen.
Phase 1: Mid Dose Treg + Tcon	Conventional T-Cells (Tcon)	Participants receive low-dose Treg (1e6 cells/kg), Tcon (1e6 cells/kg), and CD34+ HSPC following a conditioning regimen.
Phase 1: Mid Dose Treg + Tcon	Myeloablative Conditioning Regimen	Participants receive low-dose Treg (1e6 cells/kg), Tcon (1e6 cells/kg), and CD34+ HSPC following a conditioning regimen.
Phase 1: High Dose Treg + Tcon	CD34+ Hematopoietic Progenitor Cells (HSPC)	Participants receive high-dose Treg (5e6 cells/kg), Tcon (1e7 cells/kg), and CD34+ HSPC following a conditioning regimen.
Phase 1: High Dose Treg + Tcon	Regulatory T-Cells (Treg)	Participants receive high-dose Treg (5e6 cells/kg), Tcon (1e7 cells/kg), and CD34+ HSPC following a conditioning regimen.
Phase 1: High Dose Treg + Tcon	Conventional T-Cells (Tcon)	Participants receive high-dose Treg (5e6 cells/kg), Tcon (1e7 cells/kg), and CD34+ HSPC following a conditioning regimen.
Phase 1: High Dose Treg + Tcon	Myeloablative Conditioning Regimen	Participants receive high-dose Treg (5e6 cells/kg), Tcon (1e7 cells/kg), and CD34+ HSPC following a conditioning regimen.
Phase 2: Myeloablative HCT Control	Myeloablative Conditioning Regimen	Participants receive the myeloablative conditioning regimen with Treg, Tcon, or CD34+ HSPC.
Dose escalation	Conventional T cells (Tcon) and Regulatory T cells (Treg)	For the Phase I arm of the study the addition of planned numbers and ratios of Treg compared to Tcon will occur at defined time points after hematopoietic cell infusion. Each cohort will have 3 patients per group. The initial doses and ratios utilized will be 1 x 10\^6/kg of T reg cells to 3x10\^6/kg of Tcon cells at a 1:3 ratio. In order to progress to the next dose level, there must be no evidence of grade 3 or 4 acute GVHD.

Primary Outcome Measures

Name	Time	Method
GvHD free Relapse free Survival (GRFS)	12 months	GvHD-free is defined as no GvHD symptoms, and relapse free survival is defined as survival at 12 months without relapse.

Secondary Outcome Measures

Name	Time	Method
Dose-limiting toxicity (DLT)	28 days	Dose-limiting Toxicity (DLT) was assessed as: * Absolute neutrophil count \<500/µL, to 28 day * Cytokine release syndrome/acute infusion reactions as CTCAE Grade 3 to 5 * Grade 3 to 4 acute GvHD. GvHD was staged as follows: * 1: Skin: rash \<25%. Liver: bilirubin (BIL) 2-3mg/dL. Gut: diarrhea (DIA) 500-1000 mL/day * 2: Skin: rash 25-50%. Liver: BIL 3-6mg/dL. Gut: DIA 1001-1500 mL/day * 3: Skin: rash \> 50%. Liver: BIL 6-15mg/dL. Gut: DIA \>1501-2000 mL/day * 4: Skin: generalized erythroderma. Liver: BIL \>15mg/dL. Gut: DIA \>2001 mL/day GvHD was graded as follows. * 1: Skin Stage 1-2; No Liver stage; No Gut stage * 2: Skin Stage 1-3 ; Liver Stage 1; +/- Gut Stage 1 * 3: Skin Stage 2-3, Liver Stage 2-4; +/- Gut Stage 2-3 * 4: Skin Stage 2-4; Liver Stage 2-4; +/- Gut Stage 2-4 The outcome is reported as the number of participants who received both Treg and Tcon cell infusions and had DLT events, per treatment level, a number without dispersion.
Overall Survival (OS)	1 year	Overall Survival (OS) at 1 year was assessed as the number of participants per treatment level that received the hematopoietic cell transplant (HCT), and remained alive 12 months later, a number without dispersion.
Concomitant Single-agent Immunosuppression	2 years	During Phase 2, stage 1, concomitant single-agent immunosuppression will be assessed as in participants receiving fresh Treg cells. The outcome is reported as number of such participants who received single-agent immunosuppression, by treatment level, a number without dispersion.
Incidence of Serious Infections	24 months	The outcome is reported as the number of serious infections per treatment level, in participants who received the hematopoietic cell transplant (HCT), a number without dispersion.
Incidence and Severity of Chronic GvHD	2 years	Incidence and severity of chronic GvHD wil be assessed in participants who received the hematopoietic cell transplant (HCT). Stage of chronic GvHD was assessed as follows. * Stage 1: Skin: rash \<25% of skin. Liver: bilirubin 2-3mg/dL. Gut: diarrhea 500-1000 mL/day * Stage 2: Skin: rash 25-50% of skin. Liver: bilirubin 3-6mg/dL. Gut: diarrhea 1001-1500 mL/day * Stage 3: Skin: rash \> 50% of skin. Liver: bilirubin 6-15mg/dL. Gut: diarrhea \>1501-2000 mL/day * Stage 4: Skin: generalized erythroderma. Liver: bilirubin \>15mg/dL. Gut: diarrhea \>2001 mL/day Grade of chronic GvHD was determined as follows. * Grade 1: Skin Stage 1-2; No Liver stage; No Gut stage * Grade 2: Skin Stage 1-3 ; Liver Stage 1; +/- Gut Stage 1 * Grade 3: Skin Stage 2-3, Liver Stage 2-4; +/- Gut Stage 2 to 3 * Grade 4: Skin Stage 2-4; Liver Stage 2-4; +/- Gut Stage 2 to 4 The outcome is reported as the number of participants by cGvHD grade and treatment level, a number without dispersion.